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Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery
Author(s) -
Meyer Philippe,
Prodromou Chrisostomos,
Liao Chunyan,
Hu Bin,
Mark Roe S,
Vaughan Cara K,
Vlasic Ignacija,
Panaretou Barry,
Piper Peter W,
Pearl Laurence H
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600060
Subject(s) - biology , hsp90 , chaperone (clinical) , activator (genetics) , atpase , microbiology and biotechnology , computational biology , biochemistry , heat shock protein , enzyme , gene , medicine , pathology
Hsp90 is a molecular chaperone essential for the activation and assembly of many key eukaryotic signalling and regulatory proteins. Hsp90 is assisted and regulated by co‐chaperones that participate in an ordered series of dynamic multiprotein complexes, linked to Hsp90s conformationally coupled ATPase cycle. The co‐chaperones Aha1 and Hch1 bind to Hsp90 and stimulate its ATPase activity. Biochemical analysis shows that this activity is dependent on the N‐terminal domain of Aha1, which interacts with the central segment of Hsp90. The structural basis for this interaction is revealed by the crystal structure of the N‐terminal domain (1–153) of Aha1 (equivalent to the whole of Hch1) in complex with the middle segment of Hsp90 (273–530). Structural analysis and mutagenesis show that binding of N‐Aha1 promotes a conformational switch in the middle‐segment catalytic loop (370–390) of Hsp90 that releases the catalytic Arg 380 and enables its interaction with ATP in the N‐terminal nucleotide‐binding domain of the chaperone.